Variant 4-70666483-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_144646.4(JCHAIN):c.8A>G(p.Asn3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

JCHAIN
NM_144646.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.474

Variant links:

Genes affected

JCHAIN (HGNC:5713): (joining chain of multimeric IgA and IgM) Enables IgA binding activity and protein homodimerization activity. Contributes to several functions, including immunoglobulin receptor binding activity; peptidoglycan binding activity; and phosphatidylcholine binding activity. Involved in several processes, including defense response to other organism; glomerular filtration; and positive regulation of respiratory burst. Located in extracellular space. Part of monomeric IgA immunoglobulin complex; pentameric IgM immunoglobulin complex; and secretory dimeric IgA immunoglobulin complex. [provided by Alliance of Genome Resources, Apr 2022]

JCHAIN links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021020979).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JCHAIN	NM_144646.4 linkuse as main transcript	c.8A>G	p.Asn3Ser	missense_variant	1/4	ENST00000254801.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JCHAIN	ENST00000254801.9 linkuse as main transcript	c.8A>G	p.Asn3Ser	missense_variant	1/4	1	NM_144646.4	P1
	ENST00000472903.5 linkuse as main transcript	n.194+4260T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250880

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135602

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460302

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726614

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.8A>G (p.N3S) alteration is located in exon 1 (coding exon 1) of the JCHAIN gene. This alteration results from a A to G substitution at nucleotide position 8, causing the asparagine (N) at amino acid position 3 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.63

DANN

Benign

0.60

DEOGEN2

Benign

0.085

T;T;T;T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.52

.;T;.;T;T;T

M_CAP

Benign

0.0029

MetaRNN

Benign

0.021

T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.0

L;L;L;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.11

N;N;N;N;N;N

REVEL

Benign

0.032

Sift

Benign

0.72

T;T;T;T;T;T

Sift4G

Benign

0.82

T;T;T;.;.;.

Polyphen

0.0080

B;B;B;.;B;.

Vest4

0.045

MutPred

0.15

Gain of disorder (P = 0.0701);Gain of disorder (P = 0.0701);Gain of disorder (P = 0.0701);Gain of disorder (P = 0.0701);Gain of disorder (P = 0.0701);Gain of disorder (P = 0.0701);

MVP

0.048

MPC

0.16

ClinPred

0.025

GERP RS

-2.7

Varity_R

0.028

gMVP

0.088

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over